Transcriptional activity of the integrated human immunodeficiency virus-1 (HIV-1) provirus is regulated by the concerted action of cellular transcription factors and the viral transactivator Tat. In the absence of Tat, HIV transcription is highly inefficient because the assembled RNA polymerase II complex cannot elongate efficiently on the viral DNA template. Tat is a unique viral transactivator that binds to an RNA stem-loop structure called TAR, which forms at the 5′ extremity of all viral transcripts. Tat binds to TAR via its C-terminal arginine-rich motif (amino acids 49-57) that is essential for RNA binding and nuclear localization. The N-terminal transactivation domain of Tat (amino acids 1-48) interacts directly with CyclinT1, a component of the positive-acting transcription elongation factor (P-TEFb) complex. CyclinT1 recruits the cyclin-dependent kinase 9 (CDK-9), the catalytic subunit of the separately identified “Tat-associated kinase” (TAK). TAK/CDK-9 hyperphosphorylates the C-terminal domain (CTD) of the large subunit of the RNA polymerase II (RNApolII), leading to increased elongation efficiency of the polymerase complex.
HIV infection is currently treated with combination therapy, including protease inhibitors and reverse transcriptase inhibitors. Such therapy prolongs life, but does not rid the body of the infection. Furthermore, drug-resistant variants arise in a significant proportion of individuals being treated. Although a number of vaccines for HIV are currently in clinical trials, none has thus far been proven to be effective in treating or preventing HIV.
Despite the availability of treatments for HIV infection, there is a need in the art for improved reagents and methods for treating this deadly disease. The present invention addresses this need.
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